Metabotropic glutamate receptors (mGluRs) are G protein-linked glutamate receptors that mediate slow synaptic responses in mammalian brain. Seven mGluR subtypes have been cloned and divided into three major groups. Group I mGluRs couple to activation of phosphoinositide hydrolysis in expression system whereas group H and group III mGluRs couple to inhibition of adenylyl cyclase. I propose to determine subcellular localization and specific physiological roles of group III mGluRs (mGluR4 and mGluR7) in the hippocampus. I have produced and characterized two sets of highly specific antibodies, one of which selectively reacts with mGluR4 and the other with mGluR7. I propose to use these antibodies for immunocytochemical analysis at the electron microscopic level to rigorously determine the pre- and postsynaptic localization of these receptors within the hippocampus. I will then use electrophysiology methods to directly test the hypothesis that mGluR-mediated depression of excitatory postsynaptic potentials (EPSPs) is mediated by a group III mGluR and determine whether the pharmacological profile of the response more closely resembles that of mGluR7 than that of mGluR4. Finally, I will test the hypothesis that activation of group III mGluRs reduces cAMP-mediated responses to activation of receptors that are positively coupled to adenylyl cyclase.